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    Summary
    EudraCT Number:2019-000710-11
    Sponsor's Protocol Code Number:SOLTI-1718
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-02-28
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2019-000710-11
    A.3Full title of the trial
    Targeting EGFR/ERBB2 with Neratinib in Hormone Receptor (HR)-positive/HER2-negative HER2-enriched advanced/metastatic breast cancer (NEREA trial)
    Terapia con Neratinib dirigida a los receptores EGFR/ERBB2 en cancer de mama metastásico con receptor hormonal-positivo/HER2-negativo y HER2-enriquecido.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study with Neratinib in Metastatic breast cancer
    Estudio clínico con Neratinib en cancer de mama metastásico
    A.3.2Name or abbreviated title of the trial where available
    NEREA
    NEREA
    A.4.1Sponsor's protocol code numberSOLTI-1718
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSOLTI
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPUMA BIOTECHNOLOGY INC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSOLTI
    B.5.2Functional name of contact pointAREA INVESTIGACION CLINICA
    B.5.3 Address:
    B.5.3.1Street AddressC/ BALMES 89 3-7
    B.5.3.2Town/ cityBARCELONA
    B.5.3.3Post code08008
    B.5.3.4CountrySpain
    B.5.4Telephone number34933436302
    B.5.5Fax number34932702383
    B.5.6E-mailregsolti@gruposolti.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Nerlynx
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNeratinib
    D.3.2Product code PB-272; HKI-272
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNeratinib
    D.3.9.1CAS number 698387-09-6
    D.3.9.3Other descriptive nameNERATINIB
    D.3.9.4EV Substance CodeSUB32232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pre and post-menopausal women and men with locally advanced or metastatic HR+/HER2-negative endocrine resistant breast cancer
    Hombres y Mujeres pre y posmenopáusicas con cáncer de mama localmente avanzado o metastásico RH+/HER2-negativo resistente al tratamiento endocrino
    E.1.1.1Medical condition in easily understood language
    Breast cancer
    Cancer de mama
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of combined Neratinib and endocrine therapy, measured as Progression-Free Survival at 6 months (PFS6) defined as the proportion of patients alive and without progression (according to RECIST v1.1 criteria) 24 weeks after randomization in HR+/HER2- HER2-E subtype advanced breast cancer defined by the PAM50 assay resistant to non steroidal aromatase inhibitors or Fulvestrant.
    Evaluar la eficacia de la combinación de neratinib y tratamiento endocrino, medida como supervivencia sin progresión a los 6 meses (SSP6), definida como la proporción de pacientes vivas y sin progresión (según los criterios RECIST v1.1) 24 semanas después de la aleatorización en el cáncer de mama avanzado RH+/HER2- de subtipo HER2-E definido por el análisis PAM50 resistente a inhibidores de la aromatasa no esteroideos o a fulvestrant.
    E.2.2Secondary objectives of the trial
    - To determine the clinical benefit of neratinib and endocrine therapy in the patient population as described above:
    - CBR6 (RECIST 1.1) at 24 weeks or 6 months, based on investigators’ assessment.
    - Overall response rate (ORR) as defined by RECIST 1.1 for patients with measurable disease
    - Progression free survival (PFS) as defined as the time from allocation to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurs first.
    - To summarize time to response and duration of response.
    - To evaluate the safety and tolerability of neratinib + letrozole in men and pre/postmenopausal women with HR+, HER2- aBC who received prior hormonal therapy for advanced disease
    - Determinar el beneficio clínico de neratinib y del tratamiento endocrino en la población de pacientes como se ha descrito anteriormente:
    - TBC6 (RECIST 1.1) a las 24 semanas o 6 meses, según la evaluación de los investigadores.
    - Tasa de respuestas globales (TRG) conforme a los criterios RECIST 1.1 en las pacientes con enfermedad mensurable.
    - Supervivencia sin progresión (SSP), que se define como el tiempo transcurrido desde la aleatorización hasta el primer episodio de progresión de la enfermedad, determinada en el laboratorio local por el investigador con arreglo a los criterios RECIST, v1.1, o hasta la muerte por cualquier causa, lo que ocurra antes.
    - Resumir el tiempo hasta la respuesta y la duración de la respuesta.
    - Evaluar la seguridad y la tolerabilidad de neratinib + letrozol en varones y mujeres pre/posmenopáusicas con CMa RH+ y HER2- que hayan recibido tratamiento hormonal previo para enfermedad avanzada.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients of both sexes, over 18 years of age with locally advanced or metastatic breast cancer with hormonal receptors and HER2-negative
    2. Postmenopausal or Premenopausal Women,
    3. No more than one previous line of chemotherapy for locally advanced or metastatic recurrent disease.
    4. Disease resistant to aromatase or fulvestrant or tamoxifen inhibitors.
    5. Subtype HER2-E according to the PAM50 analysis confirmed by the designated laboratory.
    6. ECOG ≤1.
    1. Pacientes de ambos sexos, mayores de 18 años con cáncer de mama con receptores hormonales positivos localmente avanzado o metastásico y HER2- negativo
    2. Mujeres Posmenopáusica o Premenopáusica,
    3. No más de una línea previa de quimioterapia para enfermedad recurrente localmente avanzada o metastásica.
    4. Enfermedad resistente a los inhibidores de la aromatasa o fulvestrant o tamoxifeno,
    5. Subtipo HER2-E según el análisis PAM50 confirmado por el laboratorio designado.
    6. ECOG ≤1.
    E.4Principal exclusion criteria
    1. Prior treatment with any TKI directed to ERBB2 (eg, lapatinib, afatinib, dacomitinib, neratinib, tucatinib).
    2. Previous treatment with a cumulative dose of epirubicin> 900 mg / m2 or a cumulative dose of doxorubicin> 450 mg / m2. If another anthracycline, or more than one anthracycline, has been used, the cumulative dose should not exceed 450 mg / m2 equivalent of doxorubicin.
    3. Uncontrolled heart disease
    4. Major chronic digestive disorder with diarrhea as the main symptom
    5.Women of childbearing or pregnant age
    6. Pleural effusion, pericardial effusion
    7. Uncontrolled hypercalcemia
    8. * Additional malignant neoplasm confirmed to be in progression or have needed active treatment in the last 3 years.
    9. Presence of active metastases in the CNS or carcinomatous meningitis.
    10. * History of pneumonitis (non-infectious) that has required steroids or active pneumonitis.
    11. * Previous solid organ transplant
    12. Presence of an active infection that requires systemic treatment.
    13. * Known history of human immunodeficiency virus (HIV) infection.
    14. * Known history of hepatitis B virus infection or known active hepatitis C virus infection
    15. Inability or unwillingness to swallow tablets.
    16. Known hypersensitivity to any of the components of the product under investigation, the need for combined treatment or loperamide.
    17. Patients treated with drugs that are potent inhibitors or inducers of the CYP3A isoenzyme within 5 days prior to inclusion.
    18. * Presence of a psychiatric or substance abuse disorder
    19. Being pregnant or breastfeeding
    1. Tratamiento previo con cualquier TKI dirigido a ERBB2 (p. ej., lapatinib, afatinib, dacomitinib, neratinib, tucatinib).
    2. Tratamiento previo con una dosis acumulada de epirubicina > 900 mg/m2 o una dosis acumulada de doxorubicina > 450 mg/m2. Si se ha utilizado otra antraciclina, o más de una antraciclina, la dosis acumulada no debe ser superior al equivalente a 450 mg/m2 de doxorubicina.
    3. Cardiopatía activa no controlada
    4. Trastorno digestivo crónico importante con diarrea como síntoma principal
    5.Mujer en edad fértil o embarazada
    7. Derrame pleural, derrame pericárdico o ascitis no controlados
    8. Hipercalcemia no controlada
    9. * Neoplasia maligna adicional confirmada que esté en progresión o haya necesitado tratamiento activo en los 3 últimos años.
    10. Presencia de metástasis activas en el SNC o de meningitis carcinomatosa.
    11. * Antecedentes de neumonitis (no infecciosa) que haya precisado esteroides o neumonitis activa.
    12. * Trasplante previo de órgano sólido
    13. Presencia de una infección activa que precise tratamiento sistémico.
    14. * Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH).
    15. * Antecedentes conocidos de infección por el virus de la hepatitis B o infección activa conocida por el virus de la hepatitis C
    16. Incapacidad o falta de disposición a tragar comprimidos.
    18. Hipersensibilidad conocida a cualquiera de los componentes del producto en investigación, necesidad de tratamiento combinado o loperamida.
    19. Pacientes tratadas con fármacos que sean inhibidores o inductores potentes de la isoenzima CYP3A en los 5 días previos a la inclusión.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-Free Survival at 6 months (PFS6) defined as the proportion of patients alive and without progression (according to RECIST v1.1 criteria).
    Supervivencia sin progresión a los 6 meses (SSP6), definida como la proporción de pacientes vivas y sin progresión (según los criterios RECIST v1.1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks after randomization.
    24 semanas después de la aleatorización
    E.5.2Secondary end point(s)
    1.Clinical Benefit Rate at 24 weeks or 6 months (CBR6) defined as a Complete response (CR), Partial response (PR) or Stable Disease (SD) for at least 24 weeks, as determined locally by the investigator through the use of RECIST.
    2.Overall Response rate (ORR) as determined locally by the investigator through the use of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria
    3.Progression free survival (PFS) defined as the time from allocation to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurs first.
    4.Duration of response (DoR) defined as the time from the first occurrence of a documented objective response to disease progression, as determined locally by the investigator through use of RECIST v.1.1, or death from any cause, whichever occurs first.
    5.Time to response (TtR) defined as the time from allocation to the first objective tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR.
    6.PFS on study treatment compared to PFS on prior line of therapy (pre-PFS).
    7. Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5, including dose reductions, delays and treatment discontinuations.
    1. Beneficio clínico de neratinib y del tratamiento endocrino en la población de pacientes como se ha descrito anteriormente:
    2. TBC6 (RECIST 1.1) a las 24 semanas o 6 meses, según la evaluación de los Tasa de respuestas globales (TRG) conforme a los criterios RECIST 1.1 en las pacientes con enfermedad mensurable.
    3. Supervivencia sin progresión (SSP), que se define como el tiempo transcurrido desde la aleatorización hasta el primer episodio de progresión de la enfermedad, determinada en el laboratorio local por el investigador con arreglo a los criterios RECIST, v1.1, o hasta la muerte por cualquier causa, lo 4. Tiempo hasta la respuesta
    5. Duración de la respuesta.
    6. PFS en estudio comparada con líneas previas de tratamiento.
    7. Seguridad y la tolerabilidad de neratinib + letrozol en varones y mujeres pre/posmenopáusicas con CMa RH+ y HER2- que hayan recibido tratamiento hormonal previo para enfermedad avanzada.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -6 month for CBR6
    -Rest of secondary objective will be mesure upon lost of follow up
    -6 meses para CBR6
    -el resto de objetivos secundarios serán evaluados hasta la perdida del seguimiento
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    to assess the proportion of patients who are alive without disease progression at 24 weeks based on local investigator assessment per RECIST v1.1 (PFS6) as determined locally by the investigator.
    Evaluar la proporción de pacientes vivas y sin progresión 24 semanas después sobre la base de la evaluación del investigador local según RECIST v1.1 (PFS6), según lo determinado localmente por el investigador.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Patient Last Visit
    Ultimo Paciente Ultima Visita.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 62
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The patient will follow the treatment indicated by the doctor as standard of care.
    El paciente seguirá el tratamiento que le indique su medico por practica clínica habitual
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-01
    P. End of Trial
    P.End of Trial StatusOngoing
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